Pharmacological characterisation of JNJ-78911118, a novel, centrally-penetrant, selective GluN2A antagonist.

Background and purpose: Non-selective NMDA receptor antagonism produces rapid symptom improvement in treatment-resistant depression; however, associated side effects necessitate medical oversight during administration. We hypothesised that selective GluN2A antagonism could provide similar efficacy with an improved side effect profile. Here, we report the pharmacology of JNJ-78911118, a brain-penetrant, GluN2A selective antagonist.

Experimental approach: JNJ-78911118 pharmacology and mechanism of action was characterised in vitro using fluorescence, voltage clamp and radioligand binding assays. Target engagement was measured using ex vivo receptor autoradiography, and effects on rat prefrontal cortex monoamine levels were measured using microdialysis. Synaptogenesis assays and patch clamp studies were used to demonstrate effects on synaptic plasticity. Cardiovascular safety and neurotoxicity were assessed in rats.

Key results: JNJ-78911118 blocked GluN1/2A receptors with an IC₅₀ of 44 nM and showed selectivity against GluN1/2B, 2C and 2D receptors. Systemic administration produced concentration-dependent receptor occupancy, increased prefrontal cortex monoamine levels in wild type, but not in GluN2A knockout mice, and blocked theta burst induced LTP in the hippocampus. In addition, it produced increases in dendritic complexity and synapse number in vitro, and increased mEPSC frequency in rat cortical neurons in vivo. In rat toxicological studies, no Olney's lesions were observed, but acute increases in heart rate and blood pressure were detected.

Conclusions and implications: JNJ-78911118 is a potent and selective GluN2A antagonist that reproduces the effect of known rapidly acting antidepressants (RAADs) on neurotransmitter levels and synaptic plasticity. This molecule is a powerful in vivo tool that will enhance understanding of GluN2A biology.